Palladium-catalyzed intramolecular δ-lactam formation of aryl halides and amide-enolates: Syntheses of cherylline and latifine

Article abstract of DOI:10.1021/ol0155337

(Matrix presented) Palladium-catalyzed intramolecular carbon-carbon bond formation of aryl halides and amide-enolates gave 4-arylisoquinoline derivatives in good yields, which were further converted into the isoquinoline alkaloids cheryllme and latifine.

Full text of DOI:10.1021/ol0155337

ORGANIC
LETTERS
2001
Vol. 3, No. 4
631-633
Palladium-Catalyzed Intramolecular
δ-Lactam Formation of Aryl Halides and
Amide-Enolates: Syntheses of
Cherylline and Latifine
Toshio Honda,* Hidenori Namiki, and Fumie Satoh
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received January 9, 2001
ABSTRACT
Palladium-catalyzed intramolecular carbon−carbon bond formation of aryl halides and amide-enolates gave 4-arylisoquinoline derivatives in
good yields, which were further converted into the isoquinoline alkaloids cherylline and latifine.
The palladium-catalyzed coupling reaction of aryl halides
or vinyl halides and enolates is a promising procedure to
construct the carbon framework of polycyclic compounds,
including natural products.1 Recently, a number of modifica-
tions of this strategy were developed to prove their versatility
and utility in the synthesis of structurally interesting organic
compounds. However, application of this methodology to
the synthesis of natural products, especially to isoquinoline
alkaloids, has received little attention. In 1990, Piers suc-
cessfully utilized this reaction in the synthesis of the diterpene
crinipellin B.2 Moreover, Mann employed this type of
coupling reaction for the synthesis of the basic skeleton of
huperzine A,3 and Bonjoch also reported the construction
of bridged aza-bicyclic compounds as potential starting
materials of indole alkaloids,4 independently.
In our continuing work on the synthesis of isoquinoline
alkaloids, we were interested in the synthesis of 4-aryl-
1,2,3,4-tetrahydroisoquinoline alkaloids5 cherylline (1) and
latifine (2) by employing Pd-catalyzed intramolecular cou-
pling of aryl halides and amide-enolates,1b because the
compounds having such ring systems would be expected to
exhibit potential biological activities of medicinal interest.6
(4) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225-2228.
(5) For the recent syntheses of cherylline and latifine, see: (a) Takano,
S.; Akiyama, M.; Ogasawara, K. J. Chem. Soc., Perkin Trans. 1 1985,
2447-2453. (b) Kobayashi, S.; Tokumoto, T.; Iguchi, S.; Kihara, M. J.
Chem. Res., Synop. 1986, 280-281. (c) Katakawa, J.; Yoshimatsu, H.;
Yoshida, M.; Zhang, Y.; Irie, H.; Yajima, H. Chem. Pharm. Bull. 1988,
36, 3928-3932. (d) Cuevas, J. C.; Snieckus, V. Tetrahedron Lett. 1989,
30, 5837-5840. (e) Couture, A.; Deniau, E.; Woisel, P.; Grandclaudon,
P.; Carpentier, J. F. Tetrahedron Lett. 1996, 37, 3697-3700. (f) Couture,
A.; Deniau, E.; Lebrun, S.; Grandclaudon, P. J. Chem. Soc., Perkin Trans.
1 1999, 789-794 and references therein.
(6) (a) Kohli, J. D.; Goldberg, L. I. J. Pharm. Pharmacol. 1980, 32,
225-226. (b) Poat, J. A.; Woodruff, G. N.; Watling, K. J. J. Pharm.
Pharmacol. 1978, 30, 495-497. (c) Costall, B.; Naylor, R. J. J. Pharm.
Pharmacol. 1978, 30, 514-516. (d) Jacob, J. N.; Nichols, D. E.; Kohli, J.
D.; Glock, D. J. Med. Chem. 1981, 24, 1013-1015.
(1) For the Pd-catalyzed intramolecular coupling of aryl halides and
enolates, see: (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38,
7581-7582. (b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546-6553. (c) Muratake, H.; Nakai, H. Tetrahedron Lett.
1999, 40, 2355-2358. For the Pd-catalyzed intermolecular coupling of aryl
halides and enolates, see: (d) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370 and references therein.
(2) (a) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454-3455. (b)
Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11-13.
(3) Foricher, Y.; Mann, J. Tetrahedron Lett. 2000, 41, 2007-2009.
10.1021/ol0155337 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

Scheme 1. Synthesis of Cheryllinea
Figure 1. Structures of cherylline (1) and latifine (2).
The formation of lactam rings by this methodology has
already been reported by Hartwig and co-workers to give
the desired products (Figure 2).1b They, however, mentioned
a (a) SOCl2, benzene, reflux, 100%; (b) (i) NaN3, DMF; (ii) Ph3P,
THF; (iii) H2O, reflux, 89% from 5; (c) p-benzyloxyphenylacetyl
chloride, NaHCO3, Et2O, 87%; (d) NaH, DMF, MeI, 93%; (e)
tBuOK, Pd(dba)2, dppe, dioxane, 100 °C, 81%; (f) BMS, THF, 65
°C, 91%; (g) H2, Pd-C, EtOH, 65 °C, 68%.
borane-dimethyl sulfide (BMS) complex8 provided di-O-
benzylcherylline 10, mp 144-145 °C (lit.9 mp 144-145 °C),
which was identical with the authentic sample, previously
Figure 2. Pd-catalyzed lactam formation.
Scheme 2. Synthesis of Latifinea
that reaction of 3a gave δ-lactam in poor yield, although
γ-lactam formation of 3b proceeded in good yield. We
considered that the low-yielding six-membered lactam
formation might be attributed to the weak acidity of the
methyl proton of an acetamide group or the instability of
the generated enolate.
Thus, we prepared amide 8 having a methylene group with
relatively strong acidity as follows (Scheme 1). Alcohol 4
was converted into amine 6 in four steps, via chloride 5, by
adopting Cossy’s procedure with slight modifications.7
Schotten-Baumann reaction of amine 6 with p-benzylox-
yphenylacetyl chloride gave amide 7, which was further
alkylated with methyl iodide to provide the desired amide 8
as a mixture of rotamers of the amide group in a ratio of ca.
3:2. The Pd-catalyzed intramolecular coupling reaction of 8
in the presence of 0.1 equiv of Pd(dba)2, 0.15 equiv of dppe,
t
and 1.5 equiv of BuOK in refluxing dioxane proceeded
smoothly to give six-membered lactam 9 in 81% yield,
together with a trace amount of a debromo compound. When
the reaction was carried out in the presence of Cs2CO3 as
the base, the yield of δ-lactam was much decreased (>10%).
Lactam 9 thus prepared was further transformed to the
natural product as follows. Reduction of δ-lactam 9 with
a (a) SOCl2, benzene, reflux, 100%; (b) (i) NaN3, DMF; (ii) Ph3P,
THF; (iii) H2O, reflux, 90% from 5; (c) p-benzyloxyphenylacetyl
chloride, NaHCO3, Et2O, 87%; (d) NaH, DMF, MeI, 77%; (e)
tBuOK, Pd(dba)2, dppe, dioxane, 100 °C, 54%; (f) BMS, THF,
reflux, 61%; (g) H2, EtOH, Pd-C, 65 °C, 85%.
(7) Cossy, J.; Tresnard, L.; Pardo, D. G. Tetrahedron Lett. 1999, 40,
1125-1128.
632
Org. Lett., Vol. 3, No. 4, 2001

prepared by us.9 Finally, compound 10 was converted to
cherylline 1 by hydrogenolysis over 10% palladium on
carbon in 68% yield.
chiral ligand (S)-BINAP in refluxing dioxane; however, the
desired compound 9 was isolated in 42% yield with only
8% ee (based on the HPLC analysis using the chiral column
OD), together with 19% yield of the debromo compound.
The observed low enantioselectivity will be attributed to the
presence of the easily enolizable benzylic proton in the
cyclization product.10
The Pd-catalyzed intramolecular δ-lactam formation was
extended to the synthesis of latifine 2 by employing
essentially the same procedure as described above (Scheme
2). The requisite N-methylamide 14 was prepared from
alcohol 11 in six steps, via amine 12 and amide 13, as a
mixture of rotamers in a ratio of ca. 1:1. Attempted
cyclization of 14 with Pd(dba)2 under similar reaction
conditions as above gave the desired δ-lactam 15, in 54%
yield, together with the debromo compound (20%).
Although the coupling yield was lower than that for
cherylline, probably as a result of the presence of steric
hindrance with the benzyl group at the ortho-position to the
reaction site, the δ-lactam 15 was further converted to latifine
2, mp 213-215 °C (lit.5a mp 212-215 °C), by reduction
with borane-dimethyl sulfide complex, in 61% yield, fol-
lowed by hydrogenolysis5a of the resulting amine 16,
successfully. Again, the spectroscopic data of the synthetic
compound 2 are identical with those reported.5a
In summary, utilization of the Pd-catalyzed intramolecular
coupling of aryl halides and amide-enolates in the formation
of δ-lactam, leading to the synthesis of 4-arylisoquinoline
alkaloids, has been reported. Further application of this
methodology to the synthesis of other types of isoquinoline
alkaloids is now under investigation in this laboratory.
Acknowledgment. Support was provided by a Grant-in-
Aid from the Ministry of Education, Science, Sports, and
Culture of Japan.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
We also attempted a chiral induction in the coupling of 8
under similar reaction conditions using Pd(dba)2, tBuOK, and
OL0155337
(8) Honda, T.; Hoshi, M.; Kanai, K.; Tsubuki, M. J. Chem. Soc., Perkin
Trans. 1 1994, 2091-2101.
(9) Kametani, T.; Higashiyama, K.; Honda, T.; Otomasu, H. J. Chem.
Soc., Perkin Trans. 1 1982, 2935-2937 and references therein.
(10) Philippe, N.; Levacher, V.; Dupas, G.; Que´guiner, G.; Bourguignon,
J. Org. Lett. 2000, 2, 2185-2187.
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